Ancient Out-of-Africa Mitochondrial DNA Variants Associate with Distinct Mitochondrial Gene Expression Patterns

Abstract

Mitochondrial DNA (mtDNA) variants have been traditionally used as markers to trace ancient population migrations. Although experiments relying on model organisms and cytoplasmic hybrids, as well as disease association studies, have served to underline the functionality of certain mtDNA SNPs, only little is known of the regulatory impact of ancient mtDNA variants, especially in terms of gene expression. By analyzing RNA-seq data of 454 lymphoblast cell lines from the 1000 Genomes Project, we found that mtDNA variants defining the most common African genetic background, the L haplogroup, exhibit a distinct overall mtDNA gene expression pattern, which was independent of mtDNA copy numbers. Secondly, intra-population analysis revealed subtle, yet significant, expression differences in four tRNA genes. Strikingly, the more prominent African mtDNA gene expression pattern best correlated with the expression of nuclear DNA-encoded RNA-binding proteins, and with SNPs within the mitochondrial RNA-binding proteins PTCD1 and MRPS7. Our results thus support the concept of an ancient regulatory transition of mtDNA-encoded genes as humans left Africa to populate the rest of the world.

Experimental Support That Natural Selection Has Shaped the Latitudinal Distribution of Mitochondrial Haplotypes in Australian Drosophila melanogaster

“…This is also consistent with reports showing that coding variants in both the nuclear and mitochondrial genome affect gene expression patterns in humans (Birnbaum, et al 2012;Cohen, et al 2016), and recent evidence demonstrating that transcription regulators specifically bind to the human mtDNA coding region to regulate transcription (She, et al 2011;). In combination, these studies suggest that the synonymous…”

Divergent Patterns of Mitochondrial and Nuclear Ancestry Are Associated with the Risk for Preterm Birth

“…Haplogroup-defining polymorphisms are not merely markers of ancestry, and have consequences for mitochondrial function, including the regulation of mitochondrial gene expression. 12,31 Furthermore, the disruption of co-evolved nuclear and mitochondrial polymorphisms in subunits of the electron transport complexes can produce detectable cellular phenotypes. 32 Studies of conplastic animals, where the mitochondrial haplogroups have been bred into a distinct nuclear background, also show the potential for widespread changes in health, with the incidence of obesity, insulin signaling, and lifespan all affected.…”

mtDNA eQTLs and the m1A 16S rRNA modification explain mtDNA tissue-specific gene expression pattern in humans

“…. To identify possible associations of nDNA-encoded genes with differential expression patterns of mtDNA genes, the analysis focused on known SNPs (from the GTEx exome-based VCF files) in the dataset of genes with known mitochondrial RNA-binding activity (Wolf and Mootha 2014;Cohen et al 2016), in addition to transcription factors and RNA-binding proteins that were recently identified in human mitochondria but are not included in MitoCarta (i.e., c-Jun, JunD, CEBPb, Mef2D, KAT8, NFATC1, THRA) (Ardail et al 1993;Fernandez-Vizarra et al 2008;She et al 2011;Blumberg et al 2014;Lambertini et al 2015;Chatterjee et al 2016). To enable detection of possible correlations with sufficient statistical power, KAVIAR (Glusman et al 2011) was used to focus on SNPs with NCBI reference IDs.…”

“…Expression quantitative trait loci (eQTLs) have been widely used in genome-wide screens for regulatory elements (Westra and Franke 2014), yet were overlooked in the mtDNA. Previously, we and others performed in vitro transcription (Suissa et al 2009) and RNA-seq in cell culture from multiple individuals to assess the impact of human mtDNA variants on mtDNA transcription (Cohen et al 2016). Such experiments, however, assessed the impact of mtDNA variants on gene expression only in lymphoblastoid cells.…”